Defining a Role and Predicting Benefit From Platinum-Based Therapy in Breast Cancer: An Evolving Story

Abstract

There are three evolving stories that have the potential to improve outcomes for patients with localized triple-negative breast cancer (TNBC), a phenotypically defined breast cancer subtype that often occurs in individuals harboring germline BRCA1 mutations, including up to 20% of unselected individuals and 50% with a strong family history. When occurring sporadically without a germline mutation, TNBC shares many clinical and molecular features with BRCA1associated cancers, including defective DNA repair, which may be a result of methylation-induced silencing of BRCA or mutations in other genes that encode proteins involved in DNA repair. The first story, as exemplified in the article by Sikov et al that accompanies this editorial, is that the DNA–damaging agent carboplatin significantly improves the pathologic complete response (pCR) rate when added to a neoadjuvant chemotherapy regimen that includes a taxane, anthracycline, and alkylating agent, confirming the results of a similar trial. The second story involves using predictive biomarkers to identify tumors that are particularly sensitive to DNA-damaging agents, including germline mutations in genes that encode proteins that are essential for DNA damage repair and somatic markers that identify so-called BRCAness in sporadic cancers. The third story centers on using response to neoadjuvant therapy as a pharmacodynamic biomarker, exemplified by the strong inverse association between pCR in the breast and axilla and risk of recurrence. Although it is clear that platinum-containing agents are potentially useful in TNBC, it is unclear which patients benefit from them and how to best use them. The platinum story in breast cancer dates back to 1988, when Sledge et al noted partial responses in seven of 19 patients (47%) unselected for breast cancer subtype who received cisplatin as first-line therapy for metastatic disease. Other reports followed, confirming activity for cisplatin and carboplatin when used as first-line cytotoxic therapy in otherwise unselected patients, although efficacy was limited when used beyond first-line treatment, and attempts to combine platinum-containing agents with taxanes met with variable success. On the basis of preclinical data indicating synergy when platinum-based drugs were combined with trastuzumab in human epidermal growth factor receptor 2 (HER2)/neu positive disease, the carboplatin-docetaxel-trastuzumab regimen was found to be an effective adjuvant regimen, although adding carboplatin to a trastuzumab-taxane regimen in metastatic disease produced only modest clinical benefit. This brings us to the next chapter in the evolving platinum story, which includes two randomized phase II neoadjuvant trials in TNBC. The first report of the GeparSixto trial by von Minckwitz et al included 293 patients with operable and locally advanced TNBC who received weekly paclitaxel and liposomal doxorubicin plus bevacizumab, either alone or in combination with weekly carboplatin (area under the curve [AUC] 2, then reduced to AUC 1.5) for up to 18 weeks. The addition of carboplatin significantly improved the pCR rate in the breast and axilla (58% v 37%; P .05), although it also substantially increased toxicity without affecting breast conservation rates. The second study, by Sikov et al from the Alliance Clinical Trials Group, included 493 patients with operable and locally advanced TNBC who received weekly paclitaxel for 12 weeks followed by doxorubicin-cyclophosphamide every 2 weeks. Paclitaxel was given alone or in combination with carboplatin (AUC 6 every 3 weeks for four cycles); using a 2 2 factorial design, patients were also randomly assigned to receive chemotherapy alone or in combination with bevacizumab. The addition of carboplatin was associated with an improved pCR rate in the breast and axilla (54% v 41%; P .0029); similar benefits were observed in the absence (49% v 39%) and presence (60% v 43%) of bevacizumab. Although numerically more patients who were not initially considered candidates for breast conservation were deemed potential candidates after therapy when carboplatin was used (57% v 44%), the difference was not statistically significant, and the actual rates were not reported. Neither trial was adequately powered to determine carboplatin-reduced recurrence, nor were patients observed long enough to observe such a difference if it existed. Why use platinum-containing agents in TNBC? This brings us to our second evolving story, dating back to 2000, when it was recognized that BRCA-mutant cells were sensitized to the antineoplastic effects of DNA-damaging agents such as platinum, and that neoadjuvant platinum monotherapy was highly effective in BRCA mutation– associated breast cancer. It was also recognized that sporadic TNBC JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 33 NUMBER 1 JANUARY 1 2015